Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([O:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])=[O:3])=[O:6])[CH3:9]
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 20 °C
Reaction time: 72 h
Yield: 16.6 %

Procedure:
1.5 g of ethyl isocyanatoacetate was added to a solution containing 0.54 g of the product obtained in Example 8 in 10 ml of tetrahydrofuran and the solution was stirred for 3 days at 20° C. The solvent was evaporated in reduced pressure and the raw product was purified in a silica gel column using toluene-dioxane-acetic acid (8:1:1) as an eluent. Crystallization from acetone-petroleum ether yielded 0.13 g (17%) of the desired product desired, m.p. 155°-158° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2.[H][H].[H-].Cl[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Reactant: CCOC(=O)CCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)c2cccc3c(Br)ccc1c23

Procedure:
Sodium hydride (0.63 g, 0.0262 mol; 1.26 g of a 50% mineral oil suspension) was added portionwise with stirring to a solution of 6-bromo-benz[cd]indol-2(1H)-one (6.5 g, 0.0262 mol) in dry dimethylformamide (20 mL) allowing hydrogen evolution to cease before adding the next portion of hydride. To the cooled (ice-bath), stirred solution was added ethyl chloroacetate (3.53 g, 3.17 mL, 0.0288 mol) and the mixture was refluxed for 3 hr. The solvent was evaporated in vacuo and the residue was triturated with water (the mixture was stirred overnight at room temperature). The precipitate was separated by filtration, washed with water and hexane (10 mL; to remove mineral oil), dried (8.4 g) and crystallized from ethanol to give the title compound (5.8 in two crops): mp 128°-130° C.; Anal. Calcd for C15H12BrNO3 : C, 53.91% H, 3.62% N, 4.19%; Found: C, 53.58% H, 3.75% N, 4.26%; IR (CHCl3) 1744, 1708, 1629, 1602, and 1194 cm-1 ; UV max (methanol) 339 (ε5600), 323 (2800), 289 (sH, 4650), 279 (6200), and 258 nm (18,600);, and NMR (CDCl3)δ 1.25 (t, 3H), 4.20 (q, 2H), 4.62 (s, 2H), 6.63 (d, 1H), 7.60 (d, 1H), 7.77 (d, 1H), 8.07 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2F)=[CH:4][CH:3]=1.[F:23][CH:24]([F:27])[CH2:25][OH:26].CC([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[O:26][CH2:25][CH:24]([F:27])[F:23])=[CH:4][CH:3]=1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Reactant: OCC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
The subtitle compound is prepared from N-(4-bromophenyl)-2-fluoro-4-methylamino-5-nitro-benzamide, 2,2-difluoroethanol and KOtBu in analogy to example 1e.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](C#CCCOC(C3CCCCO3)=O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: O=C(OCCC#CC1CCC(COc2ccc(F)cc2)O1)C1CCCCO1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:15])=[O:14].FC1C=C(F)C=C2C=1CC/C/2=C\C(O)=O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:15])=[O:14]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Agent: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Product: O=C(Cl)/C=C1\CCc2c(F)cccc21

Procedure:
This compound was prepared in a similar manner to (E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride in Example 5f by substituting (E)-2-(4-fluoro-1-indanylidene)acetic acid (5.77 g, 0.03 mol) for (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. The resulting solution was concentrated in vacuo, and the residue was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>CS(C)=O>[CH3:13][C:14]1[N:15]([CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[CH:22]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2cccnc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (169 mg, 0.91 mmol) in 0.3 mL DMSO was added pulverized KOH (128 mg, 2.27 mmol), then after 10 min, a solution of 2-methyl-7-azaindole (100 mg, 0.76 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 144 mg (0.59 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.47-2.58 (m, 4H), 2.67 (t, J=7.0 Hz, 2H), 3.66 (t, J=4.5 Hz, 4H), 4.33 (t, J=7.0 Hz, 2H), 6.15 (s, 1H), 6.87-7.09 (m, 1H), 7.73 (dd, J=7.7 Hz, 1.3 Hz, 1H), 8.19 (dd, J=4.6 Hz, 1.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 13.51, 39.75, 54.37, 58.49, 67.18, 98.40, 116.05, 121.09, 127.47, 137.78, 141.71, 148.56. MS m/z 246.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: CC(C)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(trifluoromethyl)benzaldehyde and 4-isopropylaniline gave the title compound as a pale yellow oil.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OCC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(OCC)(=O)C>[C:20]1([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
Dissolve 2.0 g. (10 mmoles) of 1-adamantane carboxylic acid chloride in 20 ml. of ethyl ether and add to 3.0 ml. (32.9 mmoles) of aniline. Stir the mixture 15 minutes, then add 20 ml. of water and 25 ml. of ethyl acetate. Separate the layers and extract the aqueous layer several times with ethyl acetate. Combine the extracts and wash with 2N hydrochloric acid, saturated sodium bicarbonate solution, and water. Dry the extract over anhydrous sodium sulfate, filter and evaporate to a residue. Crystallize the residue from ethyl acetate to obtain the product of this example, m.p. 196°-199° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].O>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
Benzaldehyde (1b, 1.00 ml, 9.8 mmol) and cyclohexanone (37, 0.51 ml, 4.9 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.99 g (73%) of yellow crystals: mp 118-119° C. [expected mp 117° C.]; 1H NMR: δ 1.77 (m, 2H), 2.92 (t, 4H, J=5.2 Hz), 7.39 (m, 10H), 7.80 (s, 2H); 13C NMR: δ 23.1, 28.5, 128.3, 128.5, 130.2, 135.9, 136.1, 136.8, 190.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35]=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O:39][C:40](=[O:42])[CH3:41])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:35][C:29]1[CH:30]=[C:31]([CH2:41][C:40]([OH:39])=[O:42])[CH:32]=[CH:33][CH:34]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccccc1
Product: O=C(O)Cc1cccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
Prepared using the procedure in Example 56 except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol instead of 4-(3-hydroxyphenyl)-8-(trifluoromethyl) quinolin-3-yl](phenyl)methanone and 3-bromomethyl-phenyl)-acetic acid ethyl ester as the halide. MS (ES) m/z 526.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)[CH3:2].Cl[C:29](Cl)([O:31][C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[F:47][C:48]([F:52])([F:51])CO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:32]([O:31][CH2:29][C:48]([F:52])([F:51])[F:47])=[O:38])=[CH:9][CH:8]=1)[CH3:2]
Reactant: OCC(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCNCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)OCC)cc1)C(=O)OCC(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the compound obtained in Example 1, Step e (75.9 mg) in methylene chloride (2 ml) was added with triphosgene (89 mg, Tokyo Kasei Kogyo) and triethylamine (140 μl) and stirred for 2 hours under ice cooling. The reaction mixture was added with 2,2,2-trifluoroethanol (47 μl, Tokyo Kasei Kogyo) and stirred for three days. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and saturated aqueous sodium hydrogencarbonate in this order, dried over magnesium sulfate and concentrated. The obtained residue was applied to a silica gel column and eluted with hexane/ethyl acetate (5:1) to obtain the title compound (48.5 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][CH2:33][Br:34]>CC#N>[Br-:34].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][CH2:33][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Fc1ccccc1OCCCBr
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3F)(CC1)CC2
Product: [Br-]
Yield: 68.3 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0282 g, 0.0960 mmol) and 3-bromopropyl 2-fluorophenyl ether (0.0274 g, 0.118 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0345 g, 68.3%). EI-MS m/z 446(M+) Rt (1.96 min).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:7](F)=[N:8][CH:9]=[CH:10][CH:11]=2)=O)[CH2:3][CH2:2]1.Cl.Cl.[NH:15]([C@H:17]1[CH2:20][C@H:19]([NH:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:18]1)[NH2:16].C([O-])(=O)C.[K+].O1CCOCC1>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:4]2[C:6]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:15]([C@H:17]3[CH2:18][C@H:19]([NH:21][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:20]3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1cccnc1F)C1CC1
Reactant: NN[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc2sc(N[C@H]3C[C@H](n4nc(C5CC5)c5cccnc54)C3)nc2c1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
Cyclopropyl(2-fluoropyridin-3-yl)methanone (intermediate 53, 0.270 g, 1.635 mmol), N-(trans-3-hydrazinylcyclobutyl)benzo[d]thiazol-2-amine dihydrochloride (intermediate 52, 0.502 g, 1.635 mmol), and potassium acetate (0.462 ml, 7.39 mmol) were suspended in a mixture of dry dioxane (5 mL), dry ethanol (5 mL), and dry toluene (5 mL) and heated at 105° C. for 30 minutes. The temperature was lowered to 90° C. and additional potassium acetate (1.2 g, 6.6 eq) was added. The mixture was stirred for another 90 minutes. After another 3 hours the reaction was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient) followed by repurification using reverse phase HPLC and free basing (ethyl acetate/saturated sodium bicarbonate) gave the desired N-(trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.170 g, 0.470 mmol, 28.8% yield) as a white solid. M+1: 362.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87-1.20 (m, 4 H) 2.12-2.22 (m, 1 H) 2.49-2.71 (m, 2 H) 3.00-3.26 (m, 2 H) 4.36-4.58 (m, 1 H) 5.63 (quin, J=7.24 Hz, 1 H) 6.61 (br. s., 1 H) 6.89-7.12 (m, 2 H) 7.21 (br. s., 1 H) 7.53 (m, J=7.80 Hz, 2 H) 7.94 (dd, J=7.82, 1.17 Hz, 1 H) 8.39 (dd, J=4.40, 1.08 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25]([CH3:26])=[O:38])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Solvent: CO
Solvent: ClCCl
Product: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg (0.31 mmol) of the compound from Example 157 were introduced into 12 ml of dichloromethane at 0° C., 77 mg (0.31 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 120 mg (96% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([Cl:30])C(=O)C1>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1nc(Cl)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 35 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (250 mg, 0.80 mmol) was suspended in dry THF (10 mL) and 1 mol eq. of NCS (110 mg, 0.80 mmol) was added. The mixture was warmed to 35° C. and stirred in the dark overnight. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 235 mg (85% yield) of the desired product.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1cccc(N)n1)c1ccc(OCC(F)(F)F)nc1
Yield: 28 %

Procedure:
The title compound is prepared in 28% yield (75 mg, slight brown syrup) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 6-aminopicolinic acid (108 mg, 0.78 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][C:4]=1[CH3:14].[H-].[K+].C(Br)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].[C:28]1(C)C=CC=CC=1>>[CH3:28][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1[CH2:14]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: COc1c(C)cc(O)c2ccccc12
Reactant: Cc1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [H-]
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/CC1=C(C)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To dry toluene (40) are added 4-methoxy-3-methyl-1-naphthol (1.88 g) and potassium hydride (401 mg) followed by refluxing in nitrogen streams for an hour. After spontaneous cooling, geranyl bromide (1.95 g) is added and the mixture is stirred at room temperature for 24 hours. To the reaction mixture is added petroleum ether (100 ml) and the precipitated potassium bromide is filtered off and the solvent is distilled off at room temperature and under reduced pressure. The residue is dissolved in dimethylformamide (50 ml) followed by addition of bis(salicylidene)ethylenediiminocobalt(II) (100 mg). The mixture is stirred in oxygen gas streams at atmospheric temperature and pressure for one hour, after which the product is extracted with ether. The ethereal layer is washed with water and dried over anhydrous sodium sulfate, followed by distillation removal of the solvent. The residue is fractionally purified by silica gel column chromatography (developing solvent:ether-petroleum ether=1:19). The crude crystals thus obtained are recrystallized from acetone-alcohol. The above procedure yields menaquinone-2 (1.45 g) as yellow needles melting at 51° C.-53° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[N:3]=1.[H][H]>[Ni].CO>[NH2:8][C:7]1[C:6]([Cl:11])=[N:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[Cl:1]
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Solvent: CO
Product: CC(=O)Nc1nc(Cl)c(N)c(Cl)n1
Yield: 50.4 %

Procedure:
N1-(4,6-Dichloro-5-nitro-2-pyrimidinyl)acetamide (100 g, 0.40 mol) and Raney nickel (100 g, wet) were suspended in methanol (1.5 L) and stirred vigorously for 5 hours in a hydrogen atmosphere, at ordinary temperature and at normal pressure. After the nickel was filtered off, the filtrate was concentrated. The residue was crystallized from methanol/ethyl acetate, and the crystals were collected by filtration and washed with ethyl acetate, to give the title compound (44.6 g, 51%) as a brown solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30]>C1COCC1>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)=[O:30]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1c(O)cc(-c2ccccc2)oc1=O)c1ccc2ccccc2c1

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol),, THF (6 mL), 60% sodium hydride (0.028 mL, 0.688 mmol), 2-naphthoyl chloride (0.131 g, 0.688 mmol). m.p. dec. 219° C.; 1H NMR (250 MHz, DMSO-d6) δ6.92 (s, 1 H), 7.61 (m, 5 H), 7.97 (m, 6 H), 8.62 (s, 1 H), 9.61 (s, 1 H).
Reaction SMILES: [C:1]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][C@@H:22]1[C@H:28]2[C@H:29]3[C@H:38]([CH2:39][CH2:40][C@:25]2([CH2:26][CH3:27])[C:24](=[O:42])[CH2:23]1)[C@@H:37]1[C:32](=[CH:33][C:34](=[O:41])[CH2:35][CH2:36]1)[CH2:31][CH2:30]3)(=[O:20])[CH3:19]>COC(OC)(C)C>[C:18]([O:21][C@@H:22]1[C@H:28]2[C@H:29]3[C@H:38]([CH2:39][CH2:40][C@:25]2([CH2:26][CH3:27])[C:24](=[O:42])[CH2:23]1)[C@@H:37]1[C:32]([CH:33]=[C:34]([O:41][CH3:1])[CH2:35][CH2:36]1)=[CH:31][CH2:30]3)(=[O:20])[CH3:19]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 25 °C
Yield: 498.3 %

Procedure:
Pyridinium p-Toluenesulfonate (260 mg, 1.03 mmol) was added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (2 g, 5.8 mmol) in 2,2-dimethoxypropane (20 ml). The mixture was stirred under reflux for 7 h and at room temperature overnight. It was then cooled to −10° C. for 1 h. The precipitate was filtered, washed with cooled MeOH and dried under vacuum to afford 15α-acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one (1.84 g, yield: 88%).